1
Chapter 20: Chapter 20: Carboxylic Acid Derivatives: Nucleophilic Carboxylic Acid Derivatives: Nucleophilic Acyl SubstitutionAcyl Substitution
20.1: 20.1: Nomenclature of Carboxylic Acid Derivatives Nomenclature of Carboxylic Acid Derivatives (please read)(please read)
O
COHR
O
COR'R
carboxylic acid-oic acid
ester-oate
O
COR
R'
lactonecyclic ester
O
CClR
acid chloride-oyl chloride
O
COR
O
CR
acid anhydride-oic anhydride
O
CNR
R'
R''
amide-amide
O
CNR
R'
lactamcyclic amide
R''R C N
nitrile-nitrile
2
Y = a leaving group-Cl, -O2CR’, -OR’, -OH, -NR2,
20.3: General Mechanism for Nucleophilic Acyl SubstitutionMechanism occurs in two stages. The first is addition of the nucleophile to the carbonyl carbon to form a tetrahedral intermediate. The second stage in collapse of the tetrahedralintermediate to reform a carbonyl with expulsion of a leaving group (Y). There is overall substitution of the leaving group (Y)of the acid derivative with the nucleophile.
R YC
O
:Nu-H
NuC
O
Y
R R NuC
O+ Y:H
tetrahedralintermediate
H
3
20.2: 20.2: Structure and Reactivity of Carboxylic Acid DerivativesStructure and Reactivity of Carboxylic Acid Derivatives
Increasing reactivity
R ClC
O
R NC
O
R OC
O
CR'
O
R OR'C
O
esteramide acid chlorideacid anhydride
< < <
All acyl derivatives are prepared directly from the carboxylic acid.Less reactive acyl derivative (amidesand esters) are morereadily prepared frommore reactive acylderivatives (acidchlorides and anhydrides)
carboxylicacid
amide
acid chloride
acid anhydride ester amide
acid anhydride
ester amide
ester
amide
4
The reactivity of the acid derivative is related to it resonancestabilization. The C-N bond of amides is significantly stabilized through resonance and is consequently, the least reactive acid derivative. The C-Cl bond of acid chlorides is the least stabilized by resonance and is the most reactive acid derivative
R ClC
O
R NC
O
R OC
O
CR'
O
R OR'C
O
esteramide
acid chlorideacid anhydride
5
20.4: Nucleophilic Acyl Substitution in Acyl Chlorides20.4: Nucleophilic Acyl Substitution in Acyl ChloridesPreparation of acid chlorides from carboxylic acidsPreparation of acid chlorides from carboxylic acidsReagent: SOCl2 (thionyl chloride)
R OHC
O SOCl2, Δ
R ClCO
+ SO2 + HCl
Nucleophilic acyl substitution reactions of acid halides1. Anhydride formation; Acid chlorides react with carboxylic
acids to give acid anhydrides
Acid chlorides are much more reactive toward nucleophiles than alkyl chlorides
Cl
O
H2OOH
O
ClH2O
OHkrel = 1000 krel = 1
6
3. Aminolysis: Reaction of acid chlorides with ammonia, 1° or 2° amines to afford amides.
4. Hydrolysis: Acid chlorides react with water to affordcarboxylic acids
2. Alcoholysis: Acid chlorides react with alcohols to give esters.reactivity: 1° alcohols react faster than 2° alcohols, whichreact faster than 3° alcohols
7
20.5: Nucleophilic Acyl Substitution in Acid Anhydrides20.5: Nucleophilic Acyl Substitution in Acid AnhydridesPrepared from acid chlorides and a carboxylic acidPrepared from acid chlorides and a carboxylic acid
Reactions of acid anhydridesAcid anhydrides are slightly less reactive reactive that acid chlorides; however, the overall reactions are nearly identical and they can often be used interchangeably.1. Alcoholysis to give esters
2. Aminolysis to give amides
3. Hydrolysis to give carboxylic acids
8
20.6: Sources of Esters Preparation of esters (Table 20.3, p. 843)1. Fischer Esterification (Ch. 15.8
2. Reaction of acid chlorides or acid anhydrides with alcohols
3. Baeyer-Villiger oxidation of ketones (Ch. 17.16)
4. SN2 reaction of carboxylate anions with alkyl halides
9
20.7: Physical Properties of Esters. (please read) 20.8: Reactions of Esters: A Review and a Preview. Esters react with Grignard reagents to give tertiary alcohols. two equivalents of the Grignard reagents adds to the carbonylcarbon. (Ch. 14.10)
Esters are reduced by LiAlH4 (but not NaBH4) to primary alcohols.(Ch. 15.3)
10
Nucleophilic acyl substitution reactions of esters (Table 20.5).Esters are less reactive toward nucleophilic acyl substitution thanAcid chlorides or acid anhydrides.
1. Aminolysis: Esters react with ammonia, 1° amd 2° amines togive amides
2. Hydrolysis: Esters can be hydrolyzed to carboxylic acids underbasic conditions or acid-catalysis.
11
20.9: Acid-catalyzed Ester Hydrolysis. Reverse of the Fischeresterification reaction. Mechanism Fig. 20.3, p. 846-7
Protonation of the ester carbonyl accelerates nucleophic additionof water to give the tetrahedral intermediate. Protonation ofThe -OR’ group, then accelerates the expulsion of HOR.
12
20.10: Ester Hydrolysis in Base: SaponificationMechanism of the base-promoted hydrolysis, Fig. 20.4, p. 851
Why is the saponification of esters not base-catalyzed?
13
20.11: Reaction of Esters with Ammonia and Amines. Esters react with ammonia, 1°, and 2° amines to give amidesMechanism, Fig. 20.5, p. 853.
NH2 NH+ OCH3 + HOCH3
pKa~ 10 pKa~ 16
14
20.12: Amides
N H
O
H3C
CH3
N H
O
H3C
CH3
N
O
coplanar
amide bond has a largedipole moment ~ 3.5 Debye
H2O = 1.85 DNH3 = 1.5 DH3CNO2 = 3.5
The N-H bond of an amide is a good hydrogen bond donor andThe C=O is a good hydrogen bond acceptor.
R N
O
H
R N
O
H
NN
O
R
H
O
NN
R
O
H
R
N
NN
N
H
OR
H
O
H
R
R
H
O
O
R
R
H
H
O
N
H
O
15
Acidity of Amides: The resulting negative charge from deprotonation of an amide N-H, is stabilized by the carbonyl
O
H H
O
H
+ H2O
+ H3O
O
H
N
O
H
+ H2ON
O
N
O
pKa ~ 17-19
pKa ~ 15
+ H3O
CH3CH2NH2 N
O
H
H
N
O
H
O
OH
O
pKa ~ 35-40 ~ 15 ~10 ~5
Increasing reactivity
16
Synthesis of Amides: Amides are most commonly prepared fromthe reactions of ammonia, 1° or 2° amines with acids chlorides,acid anhydrides or esters. This is a nucleophilic acyl substitutionreaction.
When an acid chloride or anhydride is used, a mol of acid (HClor carboxylic acid) is produced. Since amines are bases, asecond equivalent is required (or an equivalent of anotherbase such as hydroxide or bicarbonate) is required toneutralize the acid
R ClC
O
R NC
Oacid chloride
R'NH2
R OHC
O
carboxylic acid
SOCl2
R'2NH
NH3
di-substitiuted (3°) amideR'
R'
R NH
C
O
R'
R NH2C
O
mono-substitiuted (2°) amide
unsubstitiuted (1°) amide
17
20.13: Hydrolysis of Amides.20.13: Hydrolysis of Amides. Amides are hydrolyzed to the Amides are hydrolyzed to thecarboxylic acids and aminescarboxylic acids and aminesAcid-promoted mechanism (Fig. 20.6, p. 858-9)Acid-promoted mechanism (Fig. 20.6, p. 858-9)
R NH2C
O
R OHC
O+ NH3
H3O+
Base-promoted mechanism (Fig. 20.7, p. 860)Base-promoted mechanism (Fig. 20.7, p. 860)
R NH2C
O NaOH, H2O
R OHC
O+ NH3
18
20.14: Lactams. (please read) cyclic amides-lactams (4-membered ring lactams) are important acti-bacterialagents.
N
SHN
OO
CH3
CH3
CO2H
H
N
SHN
OO
CH3
CH3
CO2H
HNH2
HON
HN
OO
HNH2
S
CO2H
CH3
Penicillin G Amoxicillin Cephalexin
20.15: Preparation of Nitriles1. Reaction of cyanide ion with 1° and 2° alkyl halides- this is
an SN2 reaction. (see Ch. 19.12, 8.1, 8.12)
2. Cyanohydrins- reaction of cyanide ion with ketones and aldehydes. (Ch. 17.7)
3. Dehydration of primary amides with SOCl2 (or P4O10)
R NH2C
O SOCl2 -or-P4O10
Primary amide
R NC
nitrileΔ
Dehydration: formal loss of H2O from the substrate
19
20.16: Hydrolysis of Nitriles. Nitriles are hydrolyzed in either aqueous acid or aqueous base to give carboxylic acids. The corresponding primary amide is an intermediate in the reaction.Base-promoted mechanism (Fig. 20.8, p. 865)
Acid-promoted hydrolysis:
20
20.17: Addition of Grignard Reagents to Nitriles. One equiv.of a Grignard Reagent will add to a nitrile. After aqueous acidwork-up, the product is a ketone.
aldehydes & ketones~ 2.8 D
C
O
δ +δ -
R
N
C δ +
δ -nitriles ~ 3.9 D
R NC
H3C MgBr
R
N
CCH3
MgBr
THF H3O+
R
NH
CCH3 R
O
CCH3
Must consider functional group compatibility; there is wide flexibility in the choice of Grignard reagents.
Na+ -CN
Br C≡N OMgBr
H3O+
CO2H
ketones
carboxylic acids
SN2
21
20.18: Spectroscopic Analysis of Carboxylic Acid DerivativesIR: typical C=O stretching frequencies for:
carboxylic acid: 1710 cm-1 ester: 1735 cm-1 amide: 1690 cm-1
aldehyde: 1730 cm-1
ketone 1715 cm-1
anhydrides 1750 and 1815 cm-1
Conjugation (C=C -bond or an aromatic ring) moves the C=O absorption to lower energy (right) by ~15 cm-1
OCH3
O
OCH3
O
OCH3
O
NH2
O
NH2
O
NH2
O
aliphatic ester1735 cm-1
conjugated ester1725 cm-1
aromatic ester1725 cm-1
aliphatic amide1690 cm-1
conjugated amide1675 cm-1
aromatic amide1675 cm-1
22
1H NMR:Protons on the -carbon (next to the C=O) of esters and amides have a typical chemical shift range of δ 2.0 - 2.5 ppm
Proton on the carbon attached to the ester oxygen atom have a typical chemical shift range of δ 3.5 - 4.5 ppm
The chemical shift of an amide N-H proton is typically between5-8 ppm. It is broad and often not observed.
3.42H, q, J= 7.0
1.13H, t, J= 7.0
2.03H, s
NH
O
CH3C N CH2CH3
Hδ= 4.1
q, J=7.2 Hz, 2H
δ= 2.0s, 3H
δ= 1.2t, J=7.2 Hz, 3H
C C
O
O C C
H
H H
H
H
H
H
H
23
13C NMR: very useful for determining the presence and nature of carbonyl groups. The typical chemical shift range for C=O carbon is δ160 - 220 ppm
Aldehydes and ketones: δ 190 - 220 ppmCarboxylic acids, esters and amides: δ 160 - 185 ppm
O
CH3C N CH2CH3
H
170.4
34.414.8
21.0
170.9
60.321.0
14.2O
CH3C O CH2CH3
CDCl3
CDCl3
24
Nitriles have a sharp IR CN absorption near 2250 cm1 for alkyl
nitriles and 2230 cm1 for aromatic
and conjugated nitriles (highly diagnostic)
The nitrile function group is invisible in the 1H NMR. The effect of a nitrile on the chemical shift of the protons on the -carbon is similar to that of a ketone.
The chemical shift of the nitrile carbon in the 13C spectrum isin the range of ~115-130 (significant overlap with thearomatic region).
C N
C CH3C
H
H3C
C
H
H
N
= 119C N
25
C11H12O2
118.2144.5 134.9
130.2128.8127.9
CDCl3166.9
60.514.3
7.71H, d, J= 15.0
6.41H, d, J= 15.0
7.52H, m
7.33H, m
4.22H, q, J= 7.0
1.33H, t, J= 7.0
1H NMR
13C NMR
TMS
IR
26
C10H11N
7.3(5H, m)
3.72(1H, t, J=7.1)
1.06(3H, t, J=7.4)
1.92(2H, dq, J=7.4, 7.1)
CDCl3TMS120.7
129.0128.0127.3
135.8
38.929.2
11.4